gms | German Medical Science

Objective: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. In past decades, most research focused onclarifying the mechanisms of acute brain damage. There is, however, increasing evidence that TBI pathology may continue for years after the initial insult causing progressive histopathological changes which have been linked to long term functional deficits, including progressive neurocognitive decline and psychological abnormalities. In order to identify putative therapeutic strategies for long term sequelae of TBI we need to know more mechanisms and time course of chronic posttraumatic brain damage. The aim of the current study was to characterize functional and histopathological outcome in a mouse model of controlled cortical impact (CCI) injury, a widely used experimental model of TBI.

Methods: Male C57 BL/6N mice (n=12 per group) underwent CCI or sham operation and were observed for 15 min, 24 hours, 1,3,7 days, and 1, 3, 6, or 12 months after TBI. Neurological function was assessed over the whole observation period using test paradigms evaluating motor function (Beam Walk Test), depression like behavior (Tail Suspension Test), as well as spatial learning and memory (Barnes Maze). Histopathological outcome was assessed in order to determine tissue damagegrey and white matter abnormalities; furthermore glial scar formation, microglia activation, pericytes, and microvessels were investigated by immunohistochemistry.

Results: Experimental TBIinduced progressive deterioration of motor function compared to sham-operated or naive animals (p<0.05at all time points). TBI animals showed depression like behavior (p<0.05 at 3, 6, 9, 12 months) and massive deterioration of spatial learning and memory function, starting 3 months after TBI (p<0.05 up to 12 months). On a histopathological level, CCI led to progressive lesion formation (significant at 6, 12 months), global cerebral atrophy (maximum at 12 months) as well as significant and progressive white matter loss (at 12 months) and hippocampal atrophy starting at 7 days after trauma. Long-term traumatic damage was also associated with distinct immunohistopathological changes over time.

Conclusion: This study provides comprehensive insight about extent and time course ofchronic brain damage after experimental CCI trauma on a neurobehavioural and histopathological level. It may help to further understand the pathomechanisms of chronic TBI as well as serve as a base for further investigations